Proper control of an organism's body mass and composition is essential for survival. Disorders of this regulation (e.g., obesity) are increasingly common, and can have important medical consequences, such as insulin resistance/Type 2 diabetes mellitus, and dyslipidemias/cardiovascular disease. Until recently, relatively little was known about body mass regulation. It now is clear that the adipocyte hormone leptin plays a critical role in regulating body mass/composition. Leptin signals via the leptin receptor (LR), a type I cytokine receptor, which transmits signals by activating the associated Janus family kinase, Jak2 and downstream pathways, including Stat3 and the Erk MAP kinase. The LR is expressed on key hypothalamic nuclei that regulate food intake and energy expenditure via the synthesis and secretion of neuropeptides, as well as neuroendocrine axes that regulate production of thyroid hormone, corticosteroids and sex steroids. The insulin receptor (IR) may also have important roles in body mass regulation. The IR is expressed in the hypothalamus where it appears to have anorectogenic/catabolic effects. Protein tyrosine phosphatases (PTPs) also are key regulators of tyrosyl phosphorylation, yet the roles of specific PTPs in body mass regulation have been completely obscure. Recently, mice lacking PTP1B were found to be hypersensitive to insulin and resistant to diet-induced obesity. The former appears to be due to PTP1B regulation of IR in the periphery, but why PTP1B-/- mice are lean remains unknown. Our preliminary data indicate that PTP1B-/- mice are hypersensitive to leptin and possibly to the CNS actions of insulin. Biochemical studies show that PTP1B can directly dephosphorylate Jak2. We hypothesize that PTP1B negatively regulates hypothalamic LR and possibly, IR signaling and that loss of this regulation contributes to the altered body mass phenotype of PTP1B-/-mice. To test this hypothesis, we will use a combined biochemical, physiological, and genetic approach to (1) further define the causes, mechanism, and consequences of leptin hypersensitivity in PTP1B-/- mice; (2) determine whether PTP1B also regulates hypothalamic IR signaling and if so, the consequences of loss of this regulation on the body mass phenotype of PTP1B-/- mice; and (3) create an inducible allele of PTP1B and, by means of tissue-specific knockout/reconstitution strategies, test the contribution of loss of PTP1B in the brain and specific hypothalamic regions to the PTP1B-/- body mass phenotype. The proposed studies are part of an Investigator- Initiated Interactive Research Project Grant with Dr. Barbara Kahn, whose project focuses on the role of PTP1B in regulating insulin action in the periphery. Together, our results will have potentially important implications for understanding control of body mass, and for assessing the utility of PTP1B as a therapeutic target for obesity and/or Type 2 diabetes.